Summary

The pathophysiological mechanisms explaining the association between psoriasis and type 2
diabetes are largely unknown but it has been hypothesized that systemic inflammation found
in both psoriasis and type 2 diabetes might play a role (4). In a recent study (22) we
performed hyperinsulinaemic euglycaemic clamps and found that normal glucose-tolerant
patients with moderate to severe psoriasis had lower whole-body insulin sensitivity during
insulin stimulation compared to healthy matched controls. Thus, the increased risk of type 2
diabetes in patients with psoriasis appears to include defects in the glucose metabolism
linked to psoriasis itself. However, the methods we applied did not allow us to perform a
detailed characterization of the metabolism in patients with psoriasis. To our knowledge,
tracer technique combined with indirect calorimetry has never been applied to study hepatic
and whole body insulin sensitivity, and glucose and fat oxidation, during basal conditions
or during insulin stimulation in patients with psoriasis.

Aim of study:

We aim to investigate hepatic and whole body insulin sensitivity and glucose and fat
oxidation during both basal and insulin-stimulated conditions in patients with psoriasis.

Description

Background Psoriasis is a chronic immune-mediated inflammatory disease characterized by
uncontrolled proliferation of keratinocytes, activated dendritic cells, release of
pro-inflammatory cytokines and recruitment of T-cells to the skin (1). The prevalence of
psoriasis is 2-3% worldwide, with similar frequencies in men and women (2). Psoriasis has
been associated with components of the metabolic syndrome (3), in particular obesity and
type 2 diabetes, and patients with psoriasis are at increased risk of developing type 2
diabetes (4-8). Obesity is twice as prevalent in patients with psoriasis (9,10) and patients
are at increased risk of developing cardiovascular disease compared to the general
population (11,12). These co-morbidities are important to recognize or preferably prevent
and treat as they might lead to increased mortality.

Type 2 diabetes is a complex metabolic disorder that develops as a consequence of genetic
and environmental factors such as inadequate physical activity and obesity (13). The
incidence of type 2 diabetes is increasing worldwide (14) and there is a general agreement
that it is caused mainly by the adoption to westernized, sedentary lifestyle (13). Patients
with type 2 diabetes are characterized by decreased peripheral and hepatic insulin
sensitivity, beta cell dysfunction and impaired glucose and fat oxidation (15,16). Muscle
insulin resistance has been proposed to account for as much as 85-90% of the impairment of
the peripheral insulin sensitivity (expressed as the total body glucose disposal) in
patients with type 2 diabetes during insulin stimulation (17,18). Multiple intramyocellular
defects have been demonstrated, including impaired glucose transport and phosphorylation,
reduced glycogen synthesis, and decreased glucose oxidation as well as proximal defects in
the insulin signal transduction system (16). Similar to psoriasis, systemic inflammation
occurs in patients with type 2 diabetes (19-21).

The pathophysiological mechanisms explaining the association between psoriasis and type 2
diabetes are largely unknown but it has been hypothesized that systemic inflammation found
in both psoriasis and type 2 diabetes might play a role (4). In a recent study (22) we
performed hyperinsulinaemic euglycaemic clamps and found that normal glucose-tolerant
patients with moderate to severe psoriasis had lower whole-body insulin sensitivity during
insulin stimulation compared to healthy matched controls. Thus, the increased risk of type 2
diabetes in patients with psoriasis appears to include defects in the glucose metabolism
linked to psoriasis itself. However, the methods we applied did not allow us to perform a
detailed characterization of the metabolism in patients with psoriasis. To our knowledge,
tracer technique combined with indirect calorimetry has never been applied to study hepatic
and whole body insulin sensitivity, and glucose and fat oxidation, during basal conditions
or during insulin stimulation in patients with psoriasis.

Methods:

Prior to experimental day 1 and 2 the participants will meet in the morning following a 10
hour fast (including liquids, medication, and tobacco). No alcohol consumption or vigorous
physical activities will be permitted 48 hours before the examination, and all participants
will be requested to eat carbohydrate-rich diet the previous two days. All experiments will
be carried out in the Center for Diabetes Research, Gentofte Hospital, University of
Copenhagen, Hellerup, Denmark where the necessary equipment is available.

Experimental day 1: An intravenous glucose tolerance test (IVGTT), a DXA scan (Lunar Prodigy
Advance GE Healthcare) and a fibro scan of the liver will be performed and the second
experimental day will be scheduled. Time spent during experimental day 1 is approximately 4
hours.

Fibro scan will be performed using a Fibroscan 501® (EchoSensTM, Paris, France) to asses
fibrosis status and steatosis grade of the liver (23). Hepatic elasticity and thus fibrosis
status (expressed as kPa) will be assessed by measuring the transmission speed of the
ultrasound based on the principle that the transmission speed of vibrations passing through
liver tissue increases when hepatic fibrosis is present. Hepatic steatosis will be assessed
by a controlled attenuation parameter (CAP) (expressed as decibel per meter (dB/m)) based on
the fact that fat affects ultrasound propagation. A success rate of ≥60% and a ratio of the
interquartile range of liver stiffness to the median ≤30% will be considered reliable and
used for the final analysis. Steatosis grade was decided by cut-offs of CAP according to a
previous report by Sasso et al. (24) ≥238 dB/m for S1, ≥260 dB/m for S2, and ≥293 dB/m for
S3. Fibrosis status was decided upon by cut-offs according to a previous report by Wong et
al.(23), ≥5.7 kPa for F1, ≥7.0 kPa for F2, ≥ 8.7 kPa for F3 and ≥10.3 kPa for F4.

Experimental day 2: Hyperinsulinaemic euglycaemic clamp (HEC) combined with stable isotope
infusion, muscle and fat biopsies and indirect calorimetry. Time spent during experimental
day 1 is approximately 7 hours.

Following emptying of the urine bladder, the participants will be placed recumbently in a
bed. Two cannulas will be inserted in the cubital veins: one for collection of arterialized
blood samples and one in the contralateral vein for infusions. The forearm from which blood
samples are drawn will be wrapped in a heating blanket (50°C) throughout the experiment.
Immediately after taking background samples, a primed constant infusion of [6,6-D2]glucose
(D2-glucose) (priming bolus of 40 µmol/kg; continuous infusion rate of 0.4 µmol· min·kg-1)
and [1,1,2,3,3,-D5] glycerol (D5-glycerol) (priming bolus of 1.5 µmol/kg; continuous
infusion rate 0.1 µmol· min·kg-1) will be started (t=0 min) and maintained for 360 min to
determine glucose and glycerol kinetics in the basal and insulin-stimulated state, however
the continuous infusion rates will be changed during insulin infusion. The first
steady-state period will be defined as the last 30 min of the 120-min basal period, when the
tracer equilibria of [D2]glucose and [D5]glycerol are expected; the low grade insulin
infusion (10 mU/m2 per min) steady-state period will be defined as the last 30 min of the
first insulin clamp period (210-240 min), during which the infusion rate of D2-glucose will
be increased to 0.56 µmol· min·kg-1, and the infusion rate of D5-glycerol will be reduced to
0.05 µmol· min·kg-1. The high grade insulin infusion (40 mU/m2 per min) steady-state period
will be defined as the last 30 min of the second insulin clamp period (330-360 min), during
which the infusion rate of D2-glucose will be increased to 1.0 µmol· min·kg-1, and the
infusion rate of D5-glycerol will be reduced to 0.025 µmol· min·kg-1. Following the basal
steady-state period at the time point 120 min, a continuous insulin infusion will be
initiated and fixed at 10 mU/m2 per min, the infusion rate. At the time point 240 min the
continuous insulin infusion will be primed and raised to 40 mU/m2 per min until the time
point 360 min. A variable infusion of unlabelled glucose (180 g/l) will be used to maintain
euglycemia during insulin infusion. Plasma glucose concentrations will be monitored bedside
every 5 min during clamp using the glucose oxidase method (Yellow Springs Instrument Model
2300 STAT plus analyser, Yellow Springs, Ohio, USA). The target plasma glucose concentration
will be 5 mM. Blood samples for measuring plasma glucose and glycerol enrichments will be
drawn at baseline (0 min) and in the first steady state period (90, 100, 110 and 120 min)
and during the insulin-stimulated steady state period (330, 340, 350 and 360 min). All
isotopes will be purchased from Cambridge Isotopes Laboratories (Andover, MA). Blood samples
for measuring plasma glycerol and lactate will be drawn at baseline and in the first (90 to
120 min), second (210 to 240 min) and third (330-360 min) steady-state period. Samples for
determining plasma insulin, C-peptide and glucagon will be drawn at (0, 60, 90, 100, 110,
120, 135, 150, 165, 180, 195, 210, 220, 230, 240, 255, 270, 285, 300, 315, 330, 340, 350,
360 min). Blood samples for determining FFAs, HbA1c, total-, High Density Lipoprotein (HDL)-
-, Low Density Lipoprotein (LDL)- and Very Low Density Lipoprotein (VLDL)-cholesterol, and
triglycerides will be drawn at baseline, and blood samples for measuring FFAs in the
insulin-stimulated state will be drawn at 240 and 360 min. Urine samples will be collected
at 0, 120, 240 and 360 min.

Indirect calorimetry will be performed during basal (90-120 min), low (210-240 min) and high
grade (330-360 min) insulin-stimulated steady-state to determine oxygen consumption (V02)
and carbon dioxide production (VC02). A flow-through canopy gas analyser will be used, as
described by (25). The average gas exchange over the three 30-min steady-state periods
(basal and insulin-stimulated) will be used to calculate rates of glucose and fat oxidation.

Muscle and fat biopsies will be performed in the end of the basal (t=120 min) and high grade
insulin-stimulated (t=360 min) steady-state periods. Muscle and fat biopsies will be
obtained under local anaesthesia, from musculi vastus lateralis and subcutaneous abdominal
fat using a modified Bergström's needle (including suction) at 120 (basal) and 360 min (high
grade insulin-stimulated). Biopsies will be frozen in liquid nitrogen and stored at −80ºC
for later analysis. The total amount of extracted tissue will amount to 400-600 mg.

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Medical and Biotech [MESH] Definitions

Isotope Labeling

Techniques for labeling a substance with a stable or radioactive isotope. It is not used for articles involving labeled substances unless the methods of labeling are substantively discussed. Tracers that may be labeled include chemical substances, cells, or microorganisms.

Metformin

A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. (From Martindale, The Extra Pharmacopoeia, 30th ed, p289)

Hyperinsulinism

A syndrome with excessively high INSULIN levels in the BLOOD. It may cause HYPOGLYCEMIA. Etiology of hyperinsulinism varies, including hypersecretion of a beta cell tumor (INSULINOMA); autoantibodies against insulin (INSULIN ANTIBODIES); defective insulin receptor (INSULIN RESISTANCE); or overuse of exogenous insulin or HYPOGLYCEMIC AGENTS.

Insulin Resistance

Diminished effectiveness of INSULIN in lowering blood sugar levels: requiring the use of 200 units or more of insulin per day to prevent HYPERGLYCEMIA or KETOSIS. It can be caused by the presence of INSULIN ANTIBODIES or the abnormalities in insulin receptors (RECEPTOR, INSULIN) on target cell surfaces. It is often associated with OBESITY; DIABETIC KETOACIDOSIS; INFECTION; and certain rare conditions. (from Stedman, 25th ed)

Hydrogen

Hydrogen. The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are PROTONS. Besides the common H1 isotope, hydrogen exists as the stable isotope DEUTERIUM and the unstable, radioactive isotope TRITIUM.

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